Tuberculosis kills about 2 million people globally every year. A key defense against Mycobacterium tuberculosis (Mtb) infections is the production of nitric oxide (NO) by macrophages. Although NO controls Mtb growth, it rarely sterilizes the bacterium from the host, suggesting Mtb has mechanisms to resist NO toxicity. The Mtb proteasome is one such mechanism that is required for resistance to NO. The proteasome is a multi-subunit, barrel shaped complex that degrades proteins and is conserved in all domains of life. In addition to providing resistance to NO, the Mtb proteasome is necessary to cause lethal infections in mice. We are currently trying to understand how proteolysis is linked to NO resistance as well as protecting Mtb against other host defenses. We have made two substantial discoveries during our studies: the Mtb proteasome regulates (1) the stability of an enzyme predicted to catalyze the production of cytokinins, the activity of which is linked to NO resistance; and (2) the expression of a novel copper-resistance regulon. We are working to characterize how the proteasome participates in these pathways, the knowledge of which may help us better understand the pathogenesis of one of the world's deadliest diseases.